Relationship between Neutrophil-Lymphocyte Ratio and Cardiac Autonomic Neuropathy in Diabetes Mellitus Type 2 Patients | Nurlaelatiningsih | International Journal of Integrated Health Sciences 961 4184 2 PB
Original Article
Correlation between Neutrophil-Lymphocyte Ratio and Cardiac
Autonomic Neuropathy in Diabetes Mellitus Type 2 Patients
Cahyandari Nurlaelatiningsih,1,2 Sunaryo Barki Sastradimaja,2 Irma Ruslina Defi2
1
Dr. Slamet Garut Hospital, Garut, West Java, Indonesia
Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Universitas Padjadjaran-Dr. Hasan
Sadikin General Hospital, Bandung, Indonesia
2
Abstract
Objective: To analyze the correlation between cardiac autonomic neuropathy
(CAN) and neutrophil-lymphocyte ratio (NLR) in DM type 2 patients.
Methods: This was a cross-sectional study which was conducted at the
Internal Medicine Clinic of Dr. Hasan Sadikin General Hospital, Bandung
and Chronic Disease Management (CDM) Club in Garut District, West Java,
Indonesia from October to December 2015. Subjects were 57 DM type 2
patients who met the inclusion criteria. Cardiac autonomic neuropathy
examination and complete blood count (CBC) were performed to discover the
subjects’ neutrophil-lymphocyte ratio.
Results: A strong correlation was found between CAN in DM type 2 patients
and NLR (r=0.679; p=0.000) based on Rank Spearman correlation test. The
NLR to CAN cut off point was 1.34.
Received:
December 14, 2016
Revised:
February 5, 2017
Accepted:
February 27, 2017
Conclusions: NLR examination can be used as an indicator of CAN in DM type
2 patients with NLR cut off point. There was a correlation between CAN and
DM type 2 diagnosis duration.
Keywords: Cardiac autonomic neuropathy, diabetes mellitus type 2, Ewing
test, neutrophil-lymphocyte ratio
pISSN: 2302-1381; eISSN: 2338-4506; http://doi.org/10.15850/ijihs.v5n1.961
IJIHS. 2017;5(1):15–20
Introduction
Diabetes mellitus (DM) is a complication of
metabolical diseases that is characterized
by hyperglycemia due to insulin secretion
and disorder or their combination.1,2 In this
disease, hyperglycemia becomes the primary
risk factor for micro- or macroangiopathy
complications. It also augments the oxidative
and nitrosative stress that leads to neuron
dysfunctions. Because endothelial dysfunction
causes ischemic neuron, the condition may be
worsened.
Axons, which contain many mitochondria,
are easily exposed. both directly or indirectly,
by oxidative and nitrosative stress. Augmented
oxidative stress stimulates poly (ADP-ribose)
Correspondence:
Cahyandari Nurlaelatiningsih, Dr. Slamet Garut Hospital,
Garut, West Java, Indonesia
Jl. Rumah Sakit Umum N0. 12 Sukakarya, Garut Kota,
Garut 44151, West Java, Indonesia
e-mail: [email protected]
polymerase (PARP) activation which activates
the polyol and hexonamine pathways and also
produces glycation and protein kinase C. This
problems cause oxidative stress exacerbation
which induces gene expression changes.
Hence, the transcription factors can cause
neuron disorders and deaths. Activation of
the pathways causes microvascular regulation
disturbances and endothelial dysfunctions,
leading to decreased neurovascular perfusion,
and cell dysfunction and apoptosis, as well.3–5
Cardiac autonomic neuropathy (CAN) is a
DM complication that is rarely noticed by the
patients. It is regarded as one of the major
factors of a higher number of morbidity and
mortality.4 A study stated that the prevalence
of CAN in DM type 2 was 34.4% while CAN
can be discovered after 1 year of DM type 2
diagnosis.6 In addition, it causes disorders in
the nerve fibers that innervate the heart and
blood vessels, leading to abnormal heart beat
and blood vessel control. In the early stage of
CAN, sub-clinical symptoms can be discovered.
International Journal of Integrated Health Sciences. 2017;5(1):15–20
15
Correlation between Neutrophil-Lymphocyte Ratio and Cardiac Autonomic Neuropathy in
Diabetes Mellitus Type 2 Patients
Therefore, the patients’ condition may worsen
because of this.4,7
Diabetes mellitus influences the majority of
the autonomic nervous systems. Vagus nerve
is autonomically considered as the longest
nerve. It also physiologically maintains 75% of
parasympathetic and sympathetic activities.
In the early stage of CAN, parasympathetic
nervous function may decrease and causes
sympathetic nervous dominance. The gradual
increase of sympathetic nervous dominance
occurs until the later stage of CAN in apex to
the lower part of of heart, namely symphatetic
nervous denervation.4
Ewing has already proposed a 5-simple noninvasive test to assess the cardiac autonomic
functions based on heart rate and blood
pressure to certain physiologic maneuvers.4
The test includes heart rate response to deep
breathing, heart rate response to standing,
heart rate response during valsalva maneuver,
blood pressure response to standing, and
blood pressure response to hand grip.
The first two tests are able to describe
parasympathetic activity disturbances while
the last two tests are useful to describe changes
in the sympathetic function. Among the five
tests, none is considered the best. However,
heart rate response to deep breathing is the
mostl frequently used because it shows high
specificity and reproducibility as well as easy
to use.4
Neutrophil-lymphocyte ratio (NLR) is used
as a marker of neutrophil and lymphocyte
balance level in body. It is regarded as the
recent indicator of systemic inflammation
status. It is simple, inexpensive, and useful for
sub-clinical inflammation diagnosis.6 Chronic
hyperglycemia in DM will increase the release
of reactive oxygen species (ROS) from the
neutrophils and decrease lymphocyte levels.
Decreased lymphocyte proliferation is caused
by lower levels of interleukin-2 (IL-2) receptor
expression in DM type 2. In addition, DM type
2 patients with uncontrolled glucose level may
experience lower lymphocytes and higher
neutrophils.
Several studies observed NLR with blood
glucose level regulation (HbA1C). The results
showed that NLR will increase if the HbA1C
value is 7%. The Higher levels of HbA1C are
associated with increased cardiovascular
complications found in DM type 2 patients.8–11
Another study examined the correlation
between NLR and insulin resistance in newly
diagnosed DM type 2 patients.12 The study
stated that NLR can increse in patients with
insulin resistance when compared to healthy
16
patients. This finding determines that higher
NLR can be used as an indicator to diagnose
insulin resistance.
This study was initiated to analyze the
correlation between NLR and CAN in DM type
2 patients using Ewing test.
Methods
This was a cross-sectional study conducted
at the Internal Medicine Clinic of Dr. Hasan
Sadikin General Hospital, Bandung and Chronic
Disease Management (CDM) Club in Garut
District, Indonesia in the period of October to
December 2015. The sampling method used
to calculate the subjects was non-intervention
consecutive sampling.
The inclusion criteria in the study were
DM type 2 patients aged 18–60 years without
cognition disturbance and ability to stand up.
The exclusion criteria were chronic diseases,
hypertension, pulmonary tuberculosis, and
acute exacerbation of chronic obstructive
pulmonary disease.
The subjects’ CAN and NLR in this study
were assessed using simultant Ewing tests.
Ewing tests performed were heart rate
response to internal respiration, position
change from sitting to standing, and blood
pressure response to standing. Meanwhile, the
subject results were assessed based on Ewing
test standard assessment.
The NLR score were described and
examined to reveal the correlation between
NLR and CAN through Ewing tests. If the
correlation between NLR and CAN was found,
the NLR cut off point would be examined to
detect the possibility of CAN incidence.
The CAN examinations in this study were
(1) heart rate response to internal respiration,
(2) heart rate response while standing, and (3)
blood pressure response to sitting. Actually,
CAN examination using Ewing tests includes
(1) heart rate response to internal respiration,
(2) heart rate response while standing, (3)
heart rate response on valsalva maneuver,
(4) blood pressure to standing, and (5) blood
pressure to grasping.
The Ewing test is considered as the most
appropriate test when compared to other
tests. The test frequently used is the heart
rate response to internal respiration due to
its higher specificity, reproducibility, as well
as efficiency.6 In this study, the subjects were
assessed by using the tests number 1, 2, and 4.
The NLR examination was conducted by
drawing 3 cc blood sample which was then
International Journal of Integrated Health Sciences. 2017;5(1):15–20
Cahyandari Nurlaelatiningsih, Sunaryo Barki Sastradimaja, et al.
subjected to the differential count test. The
differential blood counts were used to assess
neutrophil and lymphocyte ratio.
The data were statistically analyzed with p
value
Correlation between Neutrophil-Lymphocyte Ratio and Cardiac
Autonomic Neuropathy in Diabetes Mellitus Type 2 Patients
Cahyandari Nurlaelatiningsih,1,2 Sunaryo Barki Sastradimaja,2 Irma Ruslina Defi2
1
Dr. Slamet Garut Hospital, Garut, West Java, Indonesia
Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Universitas Padjadjaran-Dr. Hasan
Sadikin General Hospital, Bandung, Indonesia
2
Abstract
Objective: To analyze the correlation between cardiac autonomic neuropathy
(CAN) and neutrophil-lymphocyte ratio (NLR) in DM type 2 patients.
Methods: This was a cross-sectional study which was conducted at the
Internal Medicine Clinic of Dr. Hasan Sadikin General Hospital, Bandung
and Chronic Disease Management (CDM) Club in Garut District, West Java,
Indonesia from October to December 2015. Subjects were 57 DM type 2
patients who met the inclusion criteria. Cardiac autonomic neuropathy
examination and complete blood count (CBC) were performed to discover the
subjects’ neutrophil-lymphocyte ratio.
Results: A strong correlation was found between CAN in DM type 2 patients
and NLR (r=0.679; p=0.000) based on Rank Spearman correlation test. The
NLR to CAN cut off point was 1.34.
Received:
December 14, 2016
Revised:
February 5, 2017
Accepted:
February 27, 2017
Conclusions: NLR examination can be used as an indicator of CAN in DM type
2 patients with NLR cut off point. There was a correlation between CAN and
DM type 2 diagnosis duration.
Keywords: Cardiac autonomic neuropathy, diabetes mellitus type 2, Ewing
test, neutrophil-lymphocyte ratio
pISSN: 2302-1381; eISSN: 2338-4506; http://doi.org/10.15850/ijihs.v5n1.961
IJIHS. 2017;5(1):15–20
Introduction
Diabetes mellitus (DM) is a complication of
metabolical diseases that is characterized
by hyperglycemia due to insulin secretion
and disorder or their combination.1,2 In this
disease, hyperglycemia becomes the primary
risk factor for micro- or macroangiopathy
complications. It also augments the oxidative
and nitrosative stress that leads to neuron
dysfunctions. Because endothelial dysfunction
causes ischemic neuron, the condition may be
worsened.
Axons, which contain many mitochondria,
are easily exposed. both directly or indirectly,
by oxidative and nitrosative stress. Augmented
oxidative stress stimulates poly (ADP-ribose)
Correspondence:
Cahyandari Nurlaelatiningsih, Dr. Slamet Garut Hospital,
Garut, West Java, Indonesia
Jl. Rumah Sakit Umum N0. 12 Sukakarya, Garut Kota,
Garut 44151, West Java, Indonesia
e-mail: [email protected]
polymerase (PARP) activation which activates
the polyol and hexonamine pathways and also
produces glycation and protein kinase C. This
problems cause oxidative stress exacerbation
which induces gene expression changes.
Hence, the transcription factors can cause
neuron disorders and deaths. Activation of
the pathways causes microvascular regulation
disturbances and endothelial dysfunctions,
leading to decreased neurovascular perfusion,
and cell dysfunction and apoptosis, as well.3–5
Cardiac autonomic neuropathy (CAN) is a
DM complication that is rarely noticed by the
patients. It is regarded as one of the major
factors of a higher number of morbidity and
mortality.4 A study stated that the prevalence
of CAN in DM type 2 was 34.4% while CAN
can be discovered after 1 year of DM type 2
diagnosis.6 In addition, it causes disorders in
the nerve fibers that innervate the heart and
blood vessels, leading to abnormal heart beat
and blood vessel control. In the early stage of
CAN, sub-clinical symptoms can be discovered.
International Journal of Integrated Health Sciences. 2017;5(1):15–20
15
Correlation between Neutrophil-Lymphocyte Ratio and Cardiac Autonomic Neuropathy in
Diabetes Mellitus Type 2 Patients
Therefore, the patients’ condition may worsen
because of this.4,7
Diabetes mellitus influences the majority of
the autonomic nervous systems. Vagus nerve
is autonomically considered as the longest
nerve. It also physiologically maintains 75% of
parasympathetic and sympathetic activities.
In the early stage of CAN, parasympathetic
nervous function may decrease and causes
sympathetic nervous dominance. The gradual
increase of sympathetic nervous dominance
occurs until the later stage of CAN in apex to
the lower part of of heart, namely symphatetic
nervous denervation.4
Ewing has already proposed a 5-simple noninvasive test to assess the cardiac autonomic
functions based on heart rate and blood
pressure to certain physiologic maneuvers.4
The test includes heart rate response to deep
breathing, heart rate response to standing,
heart rate response during valsalva maneuver,
blood pressure response to standing, and
blood pressure response to hand grip.
The first two tests are able to describe
parasympathetic activity disturbances while
the last two tests are useful to describe changes
in the sympathetic function. Among the five
tests, none is considered the best. However,
heart rate response to deep breathing is the
mostl frequently used because it shows high
specificity and reproducibility as well as easy
to use.4
Neutrophil-lymphocyte ratio (NLR) is used
as a marker of neutrophil and lymphocyte
balance level in body. It is regarded as the
recent indicator of systemic inflammation
status. It is simple, inexpensive, and useful for
sub-clinical inflammation diagnosis.6 Chronic
hyperglycemia in DM will increase the release
of reactive oxygen species (ROS) from the
neutrophils and decrease lymphocyte levels.
Decreased lymphocyte proliferation is caused
by lower levels of interleukin-2 (IL-2) receptor
expression in DM type 2. In addition, DM type
2 patients with uncontrolled glucose level may
experience lower lymphocytes and higher
neutrophils.
Several studies observed NLR with blood
glucose level regulation (HbA1C). The results
showed that NLR will increase if the HbA1C
value is 7%. The Higher levels of HbA1C are
associated with increased cardiovascular
complications found in DM type 2 patients.8–11
Another study examined the correlation
between NLR and insulin resistance in newly
diagnosed DM type 2 patients.12 The study
stated that NLR can increse in patients with
insulin resistance when compared to healthy
16
patients. This finding determines that higher
NLR can be used as an indicator to diagnose
insulin resistance.
This study was initiated to analyze the
correlation between NLR and CAN in DM type
2 patients using Ewing test.
Methods
This was a cross-sectional study conducted
at the Internal Medicine Clinic of Dr. Hasan
Sadikin General Hospital, Bandung and Chronic
Disease Management (CDM) Club in Garut
District, Indonesia in the period of October to
December 2015. The sampling method used
to calculate the subjects was non-intervention
consecutive sampling.
The inclusion criteria in the study were
DM type 2 patients aged 18–60 years without
cognition disturbance and ability to stand up.
The exclusion criteria were chronic diseases,
hypertension, pulmonary tuberculosis, and
acute exacerbation of chronic obstructive
pulmonary disease.
The subjects’ CAN and NLR in this study
were assessed using simultant Ewing tests.
Ewing tests performed were heart rate
response to internal respiration, position
change from sitting to standing, and blood
pressure response to standing. Meanwhile, the
subject results were assessed based on Ewing
test standard assessment.
The NLR score were described and
examined to reveal the correlation between
NLR and CAN through Ewing tests. If the
correlation between NLR and CAN was found,
the NLR cut off point would be examined to
detect the possibility of CAN incidence.
The CAN examinations in this study were
(1) heart rate response to internal respiration,
(2) heart rate response while standing, and (3)
blood pressure response to sitting. Actually,
CAN examination using Ewing tests includes
(1) heart rate response to internal respiration,
(2) heart rate response while standing, (3)
heart rate response on valsalva maneuver,
(4) blood pressure to standing, and (5) blood
pressure to grasping.
The Ewing test is considered as the most
appropriate test when compared to other
tests. The test frequently used is the heart
rate response to internal respiration due to
its higher specificity, reproducibility, as well
as efficiency.6 In this study, the subjects were
assessed by using the tests number 1, 2, and 4.
The NLR examination was conducted by
drawing 3 cc blood sample which was then
International Journal of Integrated Health Sciences. 2017;5(1):15–20
Cahyandari Nurlaelatiningsih, Sunaryo Barki Sastradimaja, et al.
subjected to the differential count test. The
differential blood counts were used to assess
neutrophil and lymphocyte ratio.
The data were statistically analyzed with p
value